Spinophilin regulates central angiotensin II-mediated effect on blood pressure

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Item Type:	Article
Title:	Spinophilin regulates central angiotensin II-mediated effect on blood pressure
Creators Name:	da Costa Goncalves, A.C., Fontes, M.A., Klussmann, E., Qadri, F., Janke, J., Gollasch, M., Schleifenbaum, J., Mueller, D., Jordan, J., Tank, J., Luft, F.C. and Gross, V.
Abstract:	Central angiotensin II (AngII) plays an important role in the regulation of the sympathetic nervous system. The underlining molecular mechanisms are largely unknown. Spinophilin (SPL) is a regulator of G protein-coupled receptor signaling. Deletion of SPL induces sympathetically mediated arterial hypertension in mice. We tested the hypothesis that SPL restrains blood pressure (BP) by regulating AngII activity. We equipped SPL(-/-) and SPL(+/+) mice with telemetric devices and applied AngII (1.0 mg kg(-1) day(-1), minipumps) or the AngII subtype 1 receptor (AT1-R) blocker valsartan (50 mg kg(-1) day(-1), gavage). We assessed autonomic nervous system activity through intraperitoneal application of trimethaphan, metoprolol, and atropine. We also tested the effect of intracerebroventricular (icv) AngII on blood pressure in SPL(-/-) and in SPL(+/+) mice. Chronic infusion of AngII upregulates SPL expression in the hypothalamus of SPL(+/+) mice. Compared with SPL(+/+) mice, SPL(-/-) mice showed a greater increase in daytime BP with AngII (19.2 ± 0.8 vs. 13.5 ± 1.6 mmHg, p < 0.05). SPL(-/-) showed a greater depressor response to valsartan. BP and heart rate decreased more with trimethaphan and metoprolol in AngII-treated SPL(-/-) than in AngII-treated SPL(+/+) mice. SPL(-/-) mice responded more to icv AngII. Furthermore, brainstem AT1-R and AngII type 2 receptor (AT2-R) expression was reduced in SPL(-/-) mice. AngII treatment normalized AT1-R and AT2-R expression levels. In summary, our findings suggest that SPL restrains AngII-mediated sympathetic nervous system activation. SPL is a hitherto unrecognized molecule with regard to central blood pressure control and may pave the way to novel strategies for the treatment of hypertension.
Keywords:	Angiotensin II, Spinophilin, Blood Pressure Regulation, Autonomic Nervous System, Telemetry, Animals, Mice
Source:	Journal of Molecular Medicine
ISSN:	0946-2716
Publisher:	Springer
Volume:	89
Number:	12
Page Range:	1219-1229
Date:	December 2011
Official Publication:	https://doi.org/10.1007/s00109-011-0793-8
PubMed:	View item in PubMed

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